Clinical Trials Register

Summary
EudraCT Number:	2019-003034-16
Sponsor's Protocol Code Number:	GEIS-74
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2020-05-28
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Spain - AEMPS

A.2

EudraCT number

2019-003034-16

A.3

Full title of the trial

Phase I/II randomized trial of LB-100 plus doxorubicin vs. doxorubicin alone in first line of advanced soft tissue sarcomas

Ensayo fase I/II aleatorizado de LB-100 ms doxorrubicina vs. doxorrubicina sola en primera lnea de sarcomas de tejidos blandos avanzados

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Trial of LB-100 plus doxorubicin vs. doxorubicin alone in first line of advanced soft tissue sarcomas

Ensayo de LB-100 más doxorrubicina vs. doxorrubicina sola en primera lnea de sarcomas de tejidos blandos avanzados

A.3.2

Name or abbreviated title of the trial where available

ENHANCER

A.4.1

Sponsor's protocol code number

GEIS-74

A.5.4

Other Identifiers

Name:

Number:

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Grupo Español de Investigación en Sarcomas (GEIS)
B.1.3.4	Country	Spain
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Lixte Biotechnology Holdings, Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Sofpromed Investigacin Clnica, SLU
B.5.2	Functional name of contact point	Patricio Ledesma
B.5.3	Address:
B.5.3.1	Street Address	C/ Gremi d'Hortelans 11 - 3rd Floor - Office 8
B.5.3.2	Town/ city	Palma de Mallorca
B.5.3.3	Post code	07009
B.5.3.4	Country	Spain
B.5.4	Telephone number	34971439900
B.5.5	Fax number	34971570222
B.5.6	E-mail	ensayos@sofpromed.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Doxorubicina Accord
D.2.1.1.2	Name of the Marketing Authorisation holder	Accord Healthcare S.L.U.
D.2.1.2	Country which granted the Marketing Authorisation	Spain
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Doxorubicin
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Doxorubicin
D.3.9.1	CAS number	23214-92-8
D.3.9.4	EV Substance Code	SUB06391MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	LB-100
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	LB-100
D.3.9.3	Other descriptive name	LB-100
D.3.9.4	EV Substance Code	to be requested
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1.0
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Advanced/metastatic soft tissue sarcoma (undifferentiated pleomorphic sarcoma, leiomyosarcoma, myxoid and hypercellular myxoid liposarcoma, myxofibrosarcoma, NOS sarcoma, synovial sarcoma, fibrosarcoma, or malignant nerve sheath tumor)

Sarcoma de tejidos blandos avanzado/metastásico (sarcoma pleomórfico indiferenciado, leiomiosarcoma, liposarcoma mixoide y liposarcoma hipercelular mixoide, mixofibrosarcoma, sarcomas no especificados en otra categoría, sarcoma sinovial, fibrosarcoma o tumor maligno de la vaina del nervio periférico)

E.1.1.1

Medical condition in easily understood language

Advanced/metastatic soft tissue sarcoma

Sarcoma de tejidos blandos avanzado/metastásico

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	15.1
E.1.2	Level	HLGT
E.1.2	Classification code	10041299
E.1.2	Term	Soft tissue sarcomas
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

Phase I: To determine the maximum tolerated dose (MTD) of LB-100 in combination with doxorubicin, to be used as recommended phase 2 dose (RP2D).
Phase II: To comparatively evaluate the efficacy of the LB-100 plus doxorubicin combination vs. doxorubicin alone as measured by median progression-free survival (PFS).

Fase I: Determinar la dosis máxima tolerada (DMT) de LB-100 en combinación con doxorrubicina, para ser usada como dosis recomendada en la fase 2 (DRF2).
Fase II: Evaluar comparativamente la eficacia de LB-100 en combinación con doxorrubicina frente a doxorrubicina sola medida a través de la mediana de supervivencia libre de progresión (SLP).

E.2.2

Secondary objectives of the trial

Phase I:
• To evaluate the safety profile.
• To evaluate the overall response rate (ORR).
• To evaluate progression-free survival (PFS).
• To evaluate overall survival (OS).
• To evaluate quality of life.
Phase II:
• To evaluate the overall response rate (ORR).
• To evaluate overall survival (OS).
• To evaluate the safety profile.
• To evaluate quality of life.

Fase I:
• Evaluar el perfil de seguridad.
• Evaluar la tasa global de respuesta (TGR).
• Evaluar la supervivencia libre de progresin (SLP).
• Evaluar la supervivencia global (SG).
• Evaluar la calidad de vida.
Fase II:
• Evaluar la tasa global de respuesta (TGR).
• Evaluar la supervivencia global (SG).
• Evaluar el perfil de seguridad.
• Evaluar la calidad de vida.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Translational study for biomarkers

Estudio traslacional para biomarcadores

E.3

Principal inclusion criteria

1. The patient must provide written informed consent prior to performance of study-specific procedures and must be willing to comply with treatment and follow up. Informed consent must be obtained prior to start of the screening process. Procedures conducted as part of the patient’s routine clinical management (e.g. blood count, imaging tests, etc.) and obtained prior to signature of informed consent may be used for screening or baseline purposes as long as these procedures are conducted as specified in the protocol.
2. Age ≥ 18 years.
3. Diagnosis of advanced/metastatic soft tissue sarcoma (undifferentiated pleomorphic sarcoma, leiomyosarcoma, myxoid and hypercellular myxoid liposarcoma, myxofibrosarcoma, NOS sarcoma, synovial sarcoma, fibrosarcoma, or malignant nerve sheath tumor) confirmed by central pathology review.
4. Mandatory pre-treatment formalin-fixed paraffin embedded (FFPE) tumor tissue must be provided for all subjects without exception for central pathology review and the translational study. If archive biopsy is not available or is older than 3 months, the patient must be willing to have a pre-treatment re-biopsy of primary or metastatic tumor (baseline biopsy) within 28 days prior to enrollment.
5. The patient must be willing to undergo a second mandatory biopsy just before the initiation of the 3rd cycle and agree that this sample is used for the translational study.
6. Measurable disease according to RECIST v1.1 criteria.
7. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1.
8. The patient must be naïve of any previous treatment with anthracyclines (not even in adjuvant chemotherapy).
9. Adequate organ, hepatic, renal, cardiac, and hematologic function.
10. Laboratory tests as follows:
• Absolute neutrophil count ≥ 1,200/mm³
• Platelet count ≥ 100,000/mm³
• Hg > 9 g/dL
• Bilirubin ≤ 1.5 mg/dL
• PT and INR ≤ 1.5
• AST and ALT ≤ 2.5 times ULN
• Creatinine ≤ 1.5 mg/dL or estimated creatinine clearance ≥ 60 mL/min
• Blood glucose < 150 mg/dL
11. Left ventricular ejection fraction ≥ 50% by echocardiogram or MUGA scan assessed within 28 days before enrollment.
12. Females of childbearing potential must have a negative serum pregnancy test within 7 days prior to enrollment. Patients must not be pregnant or nursing at study entry.
13. Women and men of reproductive potential must have agreed to use an effective contraceptive method during study treatment and for 3 months after the last dose of study drug.

1. El paciente debe proporcionar consentimiento informado por escrito antes de que se lleve a cabo cualquier procedimiento específico para el estudio y debe estar dispuesto a cumplir con el tratamiento y el seguimiento. El consentimiento informado debe obtenerse antes de iniciar el proceso de selección. Cualquier procedimiento realizado como parte de la práctica clínica habitual (por ejemplo: recuento de glóbulos, pruebas de imagen, etc.) y obtenido antes de la firma del consentimiento informado puede usarse para propósitos de selección o basales siempre y cuando se hagan tal y como especifica el protocolo.
2. Edad ≥ 18 años.
3. Diagnóstico de sarcoma de tejidos blandos avanzado/metastásico (sarcoma pleomórfico indiferenciado, leiomiosarcoma, liposarcoma mixoide y liposarcoma mixoide hipercelular, mixofibrosarcoma, sarcomas no especificados en otra categoría, sarcoma sinovial, fibrosarcoma o tumor maligno de la vaina del nervio periférico) confirmado por revisión patológica central.
4. Tejido tumoral fijado en formaldehído y embebido en parafina, obligatorio, debe ser provisto por todos los pacientes sin excepción para revisión patológica central y para el estudio traslacional. Si no hay biopsia de archivo disponible o es anterior a 3 meses, el paciente debe estar dispuesto a someterse a una nueva biopsia previa al tratamiento, del tumor primario o del tumor metastásico (biopsia basal) en los 28 días previos al reclutamiento.
5. El paciente debe estar dispuesto a someterse a una segunda biopsia obligatoria justo antes del inicio del 3er ciclo y aceptar que esta muestra se use para el estudio traslacional.
6. Enfermedad medible de acuerdo con los criterios RECIST v1.1.
7. Estado funcional de 0-1 según el criterio del Eastern Cooperative Oncology Group (ECOG).
8. El paciente no puede haber recibido ningún tratamiento previo con antraciclinas (ni siquiera como quimioterapia adyuvante).
9. Funciones orgánica, hepática, renal, cardíaca y hematológica adecuadas.
10. Análisis de laboratorio del siguiente modo:
• Recuento absoluto de neutrófilos ≥ 1.200/mm³
• Recuento de plaquetas ≥ 100.000/mm³
• Hg > 9 g/dL
• Bilirrubina ≤ 1,5 mg/dL
• TP y INR ≤ 1,5
• AST y ALT ≤ 2,5 veces LSN
• Creatinina ≤ 1,5 mg/dL o aclaramiento de creatinina ≥ 60 mL/min
• Glucosa en sangre < 150 mg/dL
11. Fracción de eyección del ventrículo izquierdo ≥ 50% por ecocardiograma o exploración MUGA evaluada dentro de los 28 días previos al reclutamiento.
12. Las mujeres en edad fértil deben tener una prueba de embarazo en suero negativa dentro de los 7 días previos al reclutamiento. Las pacientes no deben estar embarazadas o amamantando al ingresar al estudio.
13. Las mujeres y los hombres en edad fértil deben estar de acuerdo con usar métodos anticonceptivos efectivos durante el tratamiento del estudio así como también durante los 3 meses posteriores a la última dosis del fármaco del estudio.

E.4

Principal exclusion criteria

1. Diagnosis different from the elegible histological subtypes.
2. Previous treatment with doxorubicin, epirubicin, idarubicin, and/or other anthracyclines or any other systemic therapy. The exception is previous systemic therapy for a previous neoplasm (see exclusion criteria 10), if this is controlled, as long as it did not include anthracyclines.
3. Uncontrolled intercurrent illness including (not limited to): symptomatic congestive heart failure (CHF) (New York Heart Association [NYHA] III/IV), unstable angina pectoris or coronary angioplasty, or stenting within 24 weeks prior to registration, unstable cardiac arrhythmia (ongoing cardiac dysrhythmias of NCI CTCAE version 5.0 Grade >= 2), known psychiatric illness that would limit study compliance, intra-cardiac defibrillators, known cardiac metastases, or abnormal cardiac valve morphology (>= Grade 3).
4. HBV and HCV serologies must be performed prior to inclusion. If HbsAg is positive it is recommended to reject the existence of replicative phase (HbaAg+, DNA VHB+). If these were positives the inclusion is not recommended, remaining at investigators’ discretion the preventive treatment with lamivudine. If a potential patient is positive for anti-HCV antibodies, presence of the virus should be ruled out with a qualitative PCR, or the patient should NOT be included in the study (if a qualitative PCR cannot be performed then patient will not be able to enter the study).
5. Any of the following diseases/illnesses within the previous 6 months:
• Myocardial infarction
• Severe or unstable angina
• Coronary or peripheral artery bypass graft
• Cerebrovascular accident or transient ischemic attack (TIA)
• Pulmonary embolism
6. Evidence of a bleeding diathesis.
7. Ongoing cardiac dysrhythmias > Grade 2.
8. Prolonged QTc interval (i.e., QTc > 450 msec for males or QTc > 470 msec for females) on baseline ECG.
9. History of allergy to study drug components.
10. History of another cancer with the exception of adequately treated basal cell carcinoma or in situ cervical cancer, or with a relapse-free interval longer than 3 years after treatment of the primary cancer with no substantial risk of recurrence.
11. Presence of brain or central nervous system metastases at the time of enrollment.
12. Patient is unwilling to provide mandatory translational tumor samples or biopsies (if required) cannot be easily taken.

1. Diagnóstico diferente a los subtipos histológicos elegibles.
2. Tratamiento previo con doxorrubicina, epirrubicina, idarrubicina y/o cualquier otra antraciclina o terapia sistémica. La excepción es terapia sistémica previa para una neoplasia (véase criterio de exclusión número 10), si está controlada, siempre y cuando no incluyese antraciclinas.
3. Enfermedad intercurrente no controlada incluyendo (sin limitarse a): insuficiencia cardíaca congestiva sintomática (ICC) (New York Heart Association [NYHA] III / IV), angina de pecho inestable o angioplastia coronaria, o colocación de stent dentro de las 24 semanas previas al registro, arritmia cardiaca inestable (arritmias cardíacas en curso de NCI CTCAE versión 5.0 Grado >= 2), enfermedad psiquiátrica conocida que limitaría el cumplimiento del estudio, desfibriladores intracardíacos, metástasis cardíacas conocidas o morfología anormal de la válvula cardíaca (>= Grado 3).
4. Las serologías de virus de la hepatitis B (VHB) y virus de la hepatitis C (VHC) deben realizarse antes de la inclusión. Si el antígeno de superficie del virus de la hepatitis B (anti-HBs) es positivo, se recomienda rechazar la existencia de fase replicativa (antígeno del core positivo (HBcAg +), ADN VHB +). Si estos fueran positivos, no se recomienda la inclusión, quedando a criterio de los investigadores el tratamiento preventivo con lamivudina. Si un paciente potencial es positivo para anticuerpos anti-VHC, la presencia del virus debe descartarse con una PCR cualitativa, o el paciente NO debe incluirse en el estudio (si no se puede realizar una PCR cualitativa, entonces el paciente no podrá entrar al estudio).
5. Cualquiera de las siguientes enfermedades o dolencias en los 6 meses previos:
• Infarto de miocardio
• Angina grave o inestable
• Injerto de derivación de arteria coronaria o periférica
• Accidente cerebrovascular o accidente isquémico transitorio
• Embolia pulmonar
6. Evidencia de diatésis hemorrágica.
7. Disritmias cardiacas en curso > Grado 2.
8. Intervalo QT corregido (QTc) prolongado (es decir, QTc > 450 ms para hombres o QTc > 470 ms para mujeres) en el ECG basal.
9. Historial de alergias a componentes de medicamentos del estudio.
10. Antecedentes de otro cáncer con la excepción de carcinoma de células basales adecuadamente tratado o un cáncer cervical in situ, o con un intervalo libre de recaída mayor de 3 años tras el tratamiento del cáncer primario sin riesgo sustancial de recurrencia.
11. Presencia de metástasis cerebrales o en el sistema nervioso central en el momento del reclutamiento.
12. El paciente no está dispuesto a proporcionar muestras tumorales traslacionales obligatorias o cuando las biopsias (si son necesarias) no se pueden tomar fácilmente.

E.5 End points

E.5.1

Primary end point(s)

Phase I:
• The MTD of LB-100 in combination with doxorubicin will be determined by assessing adverse events according to CTCAE v5.0 and they will be used as a rule for escalating or diminishing dose levels according to the dose-limiting toxicities detailed in the protocol.

Phase II:
• Progression-free survival (PFS) (according to central radiology review): Efficacy measured by median PFS according to RECIST v1.1. PFS for each patient is defined as the time in months from date of randomization to date of progression or to death due to any cause, whatever occurs first.

Fase I:
• La DMT de LB-100 en combinación con doxorrubicina se determinará evaluando los acontecimientos adversos de acuerdo con CTCAE v5.0 y estos serán usados como regla para escalar o disminuir los niveles de dosis de acuerdo con las toxicidades limitantes de dosis detalladas en el protocolo.

Fase II:
• Supervivencia libre de progresión (SLP) (según revisión radiológica central): eficacia medida por la mediana de SLP según RECIST v1.1. La SLP para cada paciente se define como el tiempo en meses desde la fecha de aleatorización hasta la fecha de progresión o muerte debido a cualquier causa, lo que ocurra primero.

E.5.1.1

Timepoint(s) of evaluation of this end point

Phase I:
- MTD: End of phase I.

Phase II:
- PFS: At the moment of progression or death.

Fase I:
- MDT: Fin de fase I.

Fase II:
- PFS: En el momento de progresión o muerte.

E.5.2

Secondary end point(s)

Phase I:
• Safety profile: Toxicity assessed by adverse events related to study drugs, detected through physical examinations and laboratory tests, and graded according to CTCAE v5.0.
• Overall Response Rate (ORR) (according to central radiology review): Efficacy measured by the ORR, which is defined as the number of subjects with a Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) divided by the number of response evaluable subjects (according to RECIST v1.1 and Choi). Choi evaluation is an exploratory task for central radiology review only.
• Progression-free survival (PFS) (according to central radiology review): Efficacy measured by median PFS according to RECIST v1.1. PFS for each patient is defined as the time in months from date of enrollment to date of progression or death due to any cause, whatever occurs first.
• Overall survival (OS): Efficacy measured by OS, which is defined as the time in months from date of enrollment to date of death due to any cause. OS will be censored on the last date a subject was known to be alive.
• Quality of life: Assessed by using the EORTC QLQ-C30 questionnaire.

Phase II:
• Overall Response Rate (ORR) (according to central radiology review): Efficacy measured by the ORR, which is defined as the number of subjects with a Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) divided by the number of response evaluable subjects (according to RECIST v1.1 and Choi). Choi evaluation is an exploratory task for central radiology review only.
• Overall survival (OS): Efficacy measured by OS, which is defined as the time in months from date of randomization to date of death due to any cause. OS will be censored on the last date a subject was known to be alive.
• Safety profile: Toxicity assessed by adverse events related to study drugs, detected through physical examinations and laboratory tests, and graded according to CTCAE v5.0.
• Quality of life: Assessed by using the EORTC QLQ-C30 questionnaire.

Fase I:
• Perfil de seguridad: toxicidad evaluada a través de los acontecimientos adversos relacionados con los fármacos del estudio, detectados a través de exámenes físicos y pruebas de laboratorio, y clasificados de acuerdo al CTCAE v5.0.
• Tasa de respuesta global (TRG) (según revisión radiológica central): eficacia medida a través de la TRG, la cual se define como el número de sujetos con la mejor respuesta global (MRG) de respuesta completa (RC) o respuesta parcial (RP) dividida entre el número de sujetos con respuesta evaluable (según RECIST v1.1 y Choi). La evaluación según Choi es una tarea exploratoria para la revisión radiológica central únicamente.
• Supervivencia libre de progresión (SLP) (según revisión radiológica central): eficacia medida por la mediana de SLP según RECIST v1.1. La SLP para cada paciente se define como el tiempo en meses desde la fecha de reclutamiento hasta la fecha de progresión o muerte debida a cualquier causa, lo que ocurra primero.
• Supervivencia global (SG): eficacia medida por SG, lo que se define como el tiempo en meses desde el reclutamiento en el ensayo hasta la fecha de muerte debido a cualquier causa. La SG será censurada en la última fecha en la que se supo que el sujeto estaba vivo.
• Calidad de vida: evaluada usando el cuestionario QLQ-C30 de la EORTC.

Fase II:
• Tasa de respuesta global (TRG) (según revisión radiológica central): eficacia medida a través de la TRG, la cual se define como el número de sujetos con una mejor respuesta global (MRG) de respuesta completa (RC) o respuesta parcial (RP) dividida entre el número de sujetos con respuesta evaluable (según RECIST v1.1 y Choi). La evaluación según Choi es una tarea exploratoria para la revisión radiológica central únicamente.
• Supervivencia global (SG): eficacia medida por SG, lo que se define como el tiempo en meses desde la fecha de aleatorización hasta la muerte debida a cualquier causa. La SG será censurada en la última fecha en que se sepa que un sujeto está vivo.
• Perfil de seguridad: toxicidad evaluada a través de los acontecimientos adversos relacionados con los fármacos del estudio, detectados a través de exámenes físicos y pruebas de laboratorio, y clasificados de acuerdo al CTCAE v5.0.
• Calidad de vida: evaluada usando el cuestionario QLQ-C30 de la EORTC.

E.5.2.1

Timepoint(s) of evaluation of this end point

Phase I:
• Safety profile: At every hospital visit.
• Overall Response Rate (ORR) (according to central radiology review): At every radiological evaluation.
• Progression-free survival (PFS) (according to central radiology review): At the moment of progression or death.
• Overall survival (OS): At the moment of death.
• Quality of life: At the end of treatment.

Phase II:
• Overall Response Rate (ORR) (according to central radiology review): At every radiological evaluation.
• Overall survival (OS): At the moment of death.
• Safety profile: At every hospital visit.
• Quality of life: At the end of treatment.

Fase I:
• Perfil de seguridad: En cada visita al hospital.
• Tasa de respuesta global (TRG) (según revisión radiológica central): En cada evaluación radiológica.
• Supervivencia libre de progresión (SLP) (según revisión radiológica central): En el momento de la progresión o muerte.
• Supervivencia global (SG): En el momento de la muerte.
• Calidad de vida: Al final del tratamiento.

Fase II:
• Tasa de respuesta global (TRG) (según revisión radiológica central): En cada evaluación radiológica.
• Supervivencia global (SG): En el momento de la muerte.
• Perfil de seguridad: En cada visita al hospital.
• Calidad de vida: Al final del tratamiento.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Quality of life

Calidad de vida

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

Maximum tolerated dose and safety

Dosis máxima tolerada y seguridad

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS (Last Visit Last Subject)

Última visita último sujeto

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1

Number of subjects for this age range:

F.1.1.1

In Utero